PROJECT SUMMARY ABSTRACT The pathologic determinants of in vivo cortical atrophy in neurodegenerative disease are not well understood due in part to the lack of magnetic resonance (MR) imaging close to death. Resolving this relationship is necessary for addressing the utility of quantitative brain imaging as an in vivo marker for disease severity and progression. Primary progressive aphasia (PPA) is a clinical language dementia syndrome that provides an ideal model for exploring the relationship between cortical atrophy and underlying pathology because it is associated with a signature pattern of asymmetric atrophy concentrated in the left hemisphere language network. This relatively focal pattern of peak atrophy allows for within-subject comparisons between damaged and relatively spared regions (e.g., left vs. right hemisphere; language vs. memory-related regions). PPA can be caused by either Alzheimer disease (AD) pathology or frontotemporal lobar degeneration pathology with a left-hemisphere dominant distribution. Amyloid- plaques (APs) and neurofibrillary tangles (NFTs) are the hallmark pathologic features of AD that are known to coincide with neuronal and synaptic loss and accumulation of activated microglia. The relationships among these markers have not been characterized in PPA with AD pathology (PPA-AD), but will be examined in this project. Specifically, Aim 1 will determine the extent and severity of cortical atrophy in five language and two non-language regions (subserving memory and visual sensation) of PPA-AD participants who had structural MR scans within 2.5 years of death. Aim 2 will quantify NFT, AP, activated microglia, neuron, and synapse densities in bilateral whole-hemisphere sections in the same regions and PPA-AD participants investigated in Aim 1 to determine the relationships among histologic markers, and their associations to in vivo measures of cortical atrophy. Our preliminary findings are consistent with our hypotheses and show that PPA-AD displays a leftward asymmetry of cortical atrophy in temporal and parietal language regions that corresponds to the highest densities of NFTs and lower densities of neurons. Combined results from this project will identify relationships among neurodegenerative features in order to discern the histopathologic basis of cortical degeneration underlying cognitive decline in PPA-AD.